Thermal ablation of focal prostate cancer (PCa) with high intensity focused ultrasound (HIFU) has recently received FDA approval as a non-invasive alternative to first-line treatment options that are still associated with significant morbidity and adverse side effects. However, current clinical transrectal HIFU systems have several limitations including the potential for collateral damage due to heat diffusion and minimal real-time ability to monitor treatment efficacy. These limitations associated with the thermal nature of the method delayed FDA approval and subsequent proliferation of this technology. Our joint team at the University of Washington (UW) and Moscow State University (MSU) has recently developed a non-thermal HIFU-based method termed boiling histotripsy (BH). The method uses sequences of milliseconds long HIFU pulses with shock fronts to mechanically fractionate targeted tissue to subcellular levels, with real-time ultrasound imaging feedback. Preliminary analysis by our joint group suggests that delivery of BH treatments with shocks may be feasible using the miniature transrectal probes similar to the existing clinical HIFU systems. The main goal of this project thus is to combine complementary strengths of the UW/MSU teams for developing the BH modality to realize effective and safe focal treatment of PCa. Specifically, we propose to determine relationships among the miniature transducer form-factor, shock wave amplitude at the focus, and BH treatment outcome through numerical modelling (performed at MSU); modeling results will guide the design (at UW) and fabrication of two HIFU probes for BH studies, one at each site. A series of experiments in ex vivo canine tissue (at UW) and human prostatic tissue from autopsy (at MSU) will be performed to develop BH exposures and provide recommendations for the design of BH treatments for future clinical trials (SA2). In SA3, the optimized treatment protocol will be applied more in the orthotopic canine PCa tumor model using a preclinical transrectal BH system developed at UW based on the results from SA1 and SA2. The initial feasibility, safety, and tolerab ility of this intervention will be evaluated in a series of acute and short-term (14 days) survival studies. Comparative morphological analysis of the treatment outcomes will be performed at UW and MSU and ultrastructural analysis will be done at MSU. Mutual visits are planned for major joint experiments on transducer characterization as well as for ex vivo and in vivo studies. We expect that the proposed method of nonthermal ablation of PCa through BH can be translated rapidly to the clinic to improve both the efficacy and safety of focal PCa therapies, thereby improving outcomes with regard to patient oncology and quality of life.